Researchers using young and old genetically engineered mice found that aging reshapes lung cancer progression: while primary tumor growth slows, metastatic spread accelerates. The mechanism centers on epigenetic activation of the integrated stress response (ISR), specifically the PERK–eIF2α–ATF4 axis. ATF4 drives epithelial and metabolic plasticity that grants cancer cells metastatic competence and creates a dependency on glutamine metabolism. Blocking ISR–ATF4 genetically or pharmacologically curtailed metastasis, while ATF4 overexpression alone was sufficient to induce it. Human clinical data confirmed ATF4 enrichment in aged lung tumors and its association with poor survival and advanced disease, pointing to actionable therapeutic targets for the most common lung cancer demographic.
